Clinicians and policymakers responsible for the care of people living with HIV in Africa lack evidence to guide decisions about whether and when to stop antimicrobial prophylaxis with trimethroprim-sulfamethoxazole (TS, co-trimoxazole) in patients who are on antiretroviral therapy (ART). Moreover, the relative importance of preventing malaria, and the extent to which any benefit of TS prophylaxis in the context of ART is due to malaria prevention, are also unknown. The overall public health objective of this clinical trial is to determine the benefit, if any, of continued TS prophylaxis after ART has been successfully initiated, and whether any such benefit is due to preventing HlV-associated opportunistic infections, malaria, or both. To address these questions, we have designed a three-arm, randomized, open-label clinical trial comparing daily TS prophylaxis for prevention of malaria and HlV-associated opportunistic infections, with weekly chloroquine prophylaxis to prevent only malaria, compared to no prophylaxis, in adults with undetectable HIV viral load and a CD4 count of >250 cells/mm3 who initiated ART within two years. The innovative study design is based in part on our observation that chloroquine-resistant malaria has disappeared from Malawi following its withdrawal from use, making it an ideal agent for malaria-specific prophylaxis. The study will allow us to determine whether persons on ART with undetectable viral load benefit from antimalarial prophylaxis, antimicrobial prophylaxis to prevent HlV-associated opportunistic infections, both, or neither. Secondary objectives focus on understanding the role that antimicrobial prophylaxis may play in maintaining viral suppression and immunologic improvement on ART, assessing the efficacy of prophylaxis in the context of highly resistant organisms, and measuring the effect of prophylaxis on the selection of drug resistance in HIV-infected persons. This research aligns directly with the strategy prioritized by the NIH Office of AIDS Research to 1) determine the optimal timing for discontinuing prophylaxis for different opportunistic infections and coinfections and 2) to evaluate strategies for prevention of prevalent opportunistic and endemic infections in the context of HIV infection. RELEVANCE (See instructions): Results of this study will be of direct and immediate relevance to decision-makers in Malawi and the region, affecting the health of millions of current and future ART recipients by providing evidence to determine 1) whether to stop TS prophylaxis in persons on ART; and 2) the importance of preventing HlV-associated opportunistic infections and malaria in persons who are stable on ART. RELEVANCE (provided by applicant): Results of this study will be of direct and immediate relevance to decision-makers in Malawi and the region, affecting the health of millions of current and future ART recipients by providing evidence to determine 1) whether to stop TS prophylaxis in persons on ART; and 2) the importance of preventing HlV-associated opportunistic infections and malaria in persons who are stable on ART.